The Haemophilus influenzae type b polysaccharide vaccine currently in use, which consists of the capsular polysaccharide, polyribosyl-ribitol-phosphate ("PRP"), confers immunity in children 18 months of age or older, but not in younger children, who are at greatest risk of Haemophilus influenzae type b caused diseases.
Attempts have been made to modify the immunological characteristics and enhance the immunogenicity of the polysaccharide by preparing polysaccharide-protein conjugate vaccines in which the PRP is coupled to a protein carrier.
The following references discuss the related art:
(1) Chu, et al., Further Studies on the Immunogenicity of Haemophilus influenzae Type b and Pneumococcal Type 6A Polysaccharide-Protein Conjugates, Infect. Immun., 40, 245-256, (1983), relates to the preparation of conjugates of each of H. influenzae type b and pneumococcal 6A polysaccharides to tetanus toxoid by a complex procedure including activation of the polysaccharide with cyanogen bromide, derivatization of the activated polysaccharide with a spacer molecule, adipic acid dihydrazide ("ADH"), and then conjugation to the protein (tentanus toxoid) with a water soluble carbodiimide to form an amido type of linkage to the protein and a complex variety of linkages from the adipic acid spacer to the polysaccharide.
(2) Jennings et al. U.S. Pat. No. 4,356,170 relates to the formation of polysaccharide-protein conjugates by the introduction of reactive aldehyde groups into the terminal residues of antigenic bacterial polysaccharides, specifically those of E. coli, meningococci, pneumococci, .beta.-hemolytic streptococci and H. influenzae, by controlled oxidation and reacting the said aldehyde residues with the free amino groups of proteins, specifically those of tetanus toxoid, diphtheria toxoid, and immunogenic protein such as .beta.-hemolytic streptococci, E. coli, H. influenzae, meningococci and pneumococci by reductive amination to covalently link said polysaccharide and protein.
(3) Anderson U.S. Pat. No. 4,673,574 relates to the formation of immunogenic conjugates comprising the reductive amination product of an immunogenic capsular polysaccharide fragment derived from the capsular polymer of Streptococcus pneumoniae or H. influenzae and containing a reducing end, prepared by means such as oxidative cleavage with periodate or by hydrolysis of a glycosidic linkage, and a bacterial toxin or toxoid as a protein carrier.
(4) Hillman et al. U.S. Pat. No. 4,459,286 relates to the preparation of a polysaccharide-protein conjugate by activation of the H. influenzae type b polysaccharide with cyanogen bromide, derivatization of the activated polysaccharide with a spacer molecule, 6-aminocaproic acid, and the conjugation of the major outer membrane protein of Neisseria meninoitidis with a water soluble carbodiimide to form an amido type of linkage to the protein and a complex variety of linkages from the 6-aminocaproic acid spacer to the polysaccharide.
(5) Gordon U.S. Pat. No. 4,496,538 relates to the production of a water-soluble covalent polysaccharide-diphtheria toxoid conjugate, wherein a pure H. influenzae type b polysaccharide is activated with cyanogen bromide and intimately mixed with diphtheria toxoid which has been derivatized with an ADH spacer.
(6) Munson, et al., Purification and Comparison of Outer Membrane Protein P2 from H. influenzae Type b Isolates, J. Clin. Invest., 72, 677-684 (1983), relates to the purification of a major outer membrane protein from H. influenzae type b which has an indicated molecular weight of 37,000 daltons and is designated P2. This major membrane protein is immunogenic and the antibody against P2 confers passive protection in young animals.
(7) Vachon, et. al., Transmembrane Permeability Channels across the Outer Membrane of H. influenzae type b, J. Bacteriol., 162, 918-924 (1985), relates to the isolation of a major protein of molecular weight 40,000 daltons ("40K") from the outer membrane of H. influenzae type b. The 40K protein acts as a porin in reconstituted vesicles by forming water-filled channels that allow the permeation of low molecular weight solutes.